ABSTRACT Down syndrome (DS) is the most common genetic cause of intellectual disability (ID). It is a significant medical and social problem because the incidence remains at one in ~700-1000 live births worldwide, and while cognitive deficits can be mild, the average IQ is 40-50. It is challenging to model DS adequately in mice because orthologs of the ~160 conserved Hsa21 protein coding genes map to three mouse chromosomes: Mmu16, 17 and 10. Here, we propose to study the Dp(10)1Yey mouse model of DS (abbreviated Dp10) that is trisomic for ~40 Hsa21 orthologs, the entirety of the Mmu10 syntenic region. Individual genes trisomic in the Dp10 affect learning and memory, astrocyte activation, cerebellar development, activity of sex hormone receptors, and/or produce sex-specific phenotypes in null mutants. Little is known however about the consequences for learning/memory (LM), and therefore, the DS cognitive phenotype, of simultaneous trisomy of the entire gene set. The single published study of Dp10 LM analyzed the performance only of 2-4 month old male mice and only in the Morris Water Maze (MWM) and context fear conditioning (CFC), and found no impairment. In contrast, in Preliminary Results, we demonstrate that, using a weaker training protocol for CFC, 3 month old male Dp10 are indeed impaired, but that females learn normally. We also show that protein expression in brains of both 3 and 8 month old Dp10 mice includes significant abnormalities in levels of components of MTOR, MAPK and apoptosis pathways, and in glutamate receptor subunits. Furthermore, the brain region-specificity of the abnormalities predominantly affects hippocampus in males and cerebellum in females. These sex differences are important because sex differences in cognitive profiles of people with DS have been reported, with males more severely impaired than females on multiple tests. Based on these observations, we hypothesize that Hsa21 orthologs of Mmu10 indeed contribute to the DS cognitive phenotype, specifically that the Dp10 mice have LM deficits, that these derive from perturbed function of brain regions in addition to or other than hippocampus, and that they differ between males and females. To test these hypotheses, we propose the following specific aims: Aim 1. We will assay male and female trisomic Dp10 and littermate controls at ~3 months of age for performance in LM tasks that require cerebellum, striatum, prefrontal cortex, and perirhinal cortex, as well as hippocampus. Aim 2. To uncover potential age related deficits, we will repeat the LM assays from Aim 1 in Dp10 mice at ~10 months of age. Results of these experiments will identify sex-specificities in the role in the DS cognitive phenotypes of the ~40 Hsa21 orthologs mapping to Mmu10. Such information is essential for rational design of preclinical evaluations of drugs for cognition in DS.